Lung cancer is the leading cause of cancer related mortality in the United States, accounting for more than one-fourth of all cancer fatalities in 2008. Although there has been substantial progress in the understanding of the molecular biology and genetics of non-small cell lung cancer (NSCLC) over the last several years, metastatic NSCLC remains incurable, and patients suffering from this disease have a median survival of ~12 months. Recently, Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib, have demonstrated clinical activity in patients with NSCLC. In particular, a small subset of patients has activating mutations in the EGFR kinase domain, and in these patients, EGFR TKIs often produce dramatic and durable responses. Unfortunately these highly sensitive cancers invariably develop resistance (acquired resistance), thereby limiting the clinical benefit from these drugs. The most commonly observed mechanism of acquired resistance is the development of a secondary mutation in EGFR, T790M. This mutation leads to increased affinity of EGFR for ATP, thereby rendering gefitinib and erlotinib ineffective competitive inhibitors. To overcome the T790M resistance mutation, the pharmaceutical and biotechnology industries have focused on developing a new class of EGFR inhibitors that irreversibly bind EGFR and have the capacity to inhibit EGFR T790M. Unfortunately, all the current second generation irreversible EGFR inhibitor under clinical development for overcoming the acquired T790M mutations have demonstrated unimpressive efficacy. This is likely due to their relative impotence against EGFR T790M (micromolar) versus their potency against wild type EGFR. Thus, the toxicity due to inhibiting wild type EGFR in the patient's skin and gastrointestinal tract limits the doses and serum concentrations of these drugs to levels that do not effectively inhibit the EGFR T790M in the resistant cancers. Founders of Gatekeeper Therapeutics, based in Cambridge Massachusetts, have developed a series of novel compounds that specifically inhibit the kinase domain EGFR mutants with T790M at single nanomolar range without any activity on the wild type EGFR. The lead compounds from this series has been successfully tested in genetically engineered cell lines, human NSCLC lines and genetically engineered lung cancer mouse models driven by mutant EGFRs. In this proposal, we seek to extend these results and move this series of compounds toward IND and clinical development with the following three aims. In aim 1, we will evaluate WZ-4002, the lead mutant specific EGFR inhibitor, for in vitro and in vivo ADME properties. In aim 2, we will generate and characterize additional WZ-4002 analogs that have more favorable pharmacokinetic properties that would be suitable for 2 week rat toxicology studies. In aim 3, we will perform 2 week rat toxicology studies on WZ-4002 or the leading analog identified in aim 2. We believe work described in this proposal will lead to a commercially valuable development of a novel small molecule EGFR mutant specific kinase inhibitor. This first in class and best in class mutant EGFR inhibitor will eventually benefit lung cancer patients and prolong their survival. PUBLIC HEALTH RELEVANCE: Lung cancer is the leading cause of all cancer related mortality in the United States. Gatekeeper Therapeutics is developing drugs which might be very efficacious and might prolong the survival of a subset of lung cancer patients that are identified by the specific genetic mutations in their cancers.